Lipid-laden macrophages (foam cells) are central to maintaining chronic tuberculosis (TB) infection. Foam cells provide a favorable niche for survival of Mycobacterium tuberculosis, because antimicrobial functions are generally down-regulated in these cells. Moreover, foam cells induce tissue damage and caseation, and facilitate TB transmission. Indeed, the extent of TB-induced tissue damage is closely correlated with foam cell abundance in lesions. The overarching hypothesis of this proposal is that blocking foam cell formation will facilitate macrophage-mediated clearance of M. tuberculosis infection. We recently discovered that, unlike the cholesteryl- ester-rich foam cells found in atherosclerotic lesions, foam-cell-rich and necrotic areas of tuberculous granulomas are particularly enriched in triglycerides. Given the different nature of the storage lipid, the underlying lipid accumulation mechanisms in tuberculous foam cells must differ substantially from those known to occur during atherogenesis. Thus, TB-specific interventions are needed to impede foam cell formation in TB. Infection with M. tuberculosis is associated with dysregulation of two cellular pathways involved in triglyceride homeostasis: the first, which is pro-lipogenic, includes two kinases, protein kinase B and mTOR complex 1 (Akt/mTORC1); the second, which is anti-lipogenic, includes AMP-activated protein kinase and the NAD+- dependent deacetylases called sirtuins (AMPK/SIRT). We propose a two-aim plan utilizing clinical samples from human donors and experimental infections of macrophages ex vivo and of a mouse strain producing necrotic tuberculous lung lesions (C3HeB/FeJ). These experiments will characterize: (i) the effect of anti-lipogenic treatments on antimycobacterial functions of human macrophages infected ex vivo; (ii) the relationship between activation of these pathways and control of clinical M. tuberculosis infection; and (iii) the role of anti-lipogenic treatments as adjunctive therapy for TB in C3HeB/FeJ mice. The overall objective of this proposal is to discover druggable targets in the pro-lipogenic and anti-lipogenic pathways, with the long-term goal of shortening the duration of TB treatment and improving TB-related immunopathology. This proposal is expected to lead to clinical trials of novel host-directed therapeutics against TB. More generally, these studies are expected to reveal the potential for pharmacological interventions targeting maladaptive macrophage responses in non-atherogenic diseases and to stimulate their pursuit.